Developing New Treatments for Tourette syndrome: Therapeutic Trials with Modulators of Glutamatergic Neurotransmission 1 R34 MH085844 ABSTRACT A joint NIH -Tourette Syndrome Association Conference has emphasized the critical need for the testing and development of new pharmacotherapy for tic suppression in Tourette syndrome (TS). This submission is a safety, tolerability and efficacy pilot study using two medications that modulate glutamate neurotransmission, riluzole, a glutamate antagonist, and D-serine, a glutamate agonist. Glutamate is the primary excitatory neurotransmitter in the central nervous system, an essential component of pathways implicated in TS and an extensive modulator of dopamine, thet major neurotransmitter associated with tics. This is a single site, short-term, proof of concept study of riluzole and D-serine for the treatment of tics. Each medication will be evaluated and compared to placebo as part of a double-blind, randomized, parallel, flexible dose, three-arm, 6-week, treatment protocol (D-serine, riluzole, or placebo). A total of sixty patients (age 8-17 years) with TS and moderate to moderately-severe tics will receive study medication according to a 2:1 (dopamine modulating drug: placebo), randomized schedule, i.e., riluzole (n=24), D- serine (n=24), placebo (n=12). The primary outcome measure is tic suppression as determined by changes in the Total Tic Subscore of the Yale Global Tic Severity Scale (YGTSS). Secondary tic outcome measures include changes in the YGTSS Total Score and two Global Impression Scales. Further, since both riluzole and D-serine have been proposed as treatments for obsessive-compulsive behaviors, a TS comorbidity, these symptoms will be followed. Safety measures include serial physical examinations, vital signs, laboratory studies (comprehensive metabolic panel, complete blood count, plasma amino acids, and urine analyses), documentation of side effects and adverse events, and measurement of changes in ADHD, depression and anxiety. This pilot investigation will provide important proof-of-concept data on glutamate therapies for TS and, in turn, evidence for large-scale, multicenter clinical trials. PUBLIC HEALTH RELEVANCE: Developing New Treatments for Tourette syndrome: Therapeutic Trials with Modulators of Glutamatergic Neurotransmission Narrative This study addresses a critical need for identifying new therapies for the treatment of Tourette syndrome. In this three-arm, parallel, double-blind, randomized, flexible dose, pilot study, we establish the safety, tolerability, and efficacy of the glutamate modulating agents riluzole (a glutamate antagonist) and D-serine (a glutamate agonists) as compared to placebo. The results of this research could have a major impact on the treatment of individuals with tic disorders.